Ligand Density and Linker Length are Critical Factors for Multivalent Nanoparticle-Receptor Interactions
Ligand Density and Linker Length are Critical Factors for Multivalent Nanoparticle-Receptor Interactions
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DOI：
10.1021/acsami.8b18843
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发表时间：
2019-01-09
影响因子：
9.5
通讯作者：
Goepferich, Achim M.
中科院分区：
文献类型：
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作者：
Abstiens, Kathrin;Gregoritza, Manuel;Goepferich, Achim M.
虽然有大量的研究可用于评估靶向聚合纳米颗粒的治疗效果，但对能够进一步影响其被靶细胞吸收的关键属性知之甚少。在本研究中，不同的cRGD配体密度（0-100%表面功能化）与不同的聚乙二醇（PEG）间隔长度（2/3.5/5 kDa）结合，并使用α (v) β(3)整合素过表达的U87MG胶质母细胞瘤细胞评估靶向核-壳结构聚乳酸-羟基乙酸/聚乳酸-PEG纳米颗粒的特异性受体结合。具有100%表面功能化的纳米颗粒和短PEG2k连接物显示出形成胶体簇的高倾向，允许与细胞膜上的整合素受体合作结合。相比之下，较长的PEG链的高柔韧性增加了配体缠结和包裹的机会，减少了配体与受体结合事件的数量。因此，短PEG2k连接体和高cRGD表面修饰的结合协同增加了纳米颗粒进入靶细胞的摄取。尽管到目前为止，纳米颗粒的大小及其功能化程度被认为是控制靶向胶体摄取效率的主要决定因素，但这些结果强烈表明，在设计靶向药物递送配方时，应仔细考虑连接体长度的作用，以最大限度地提高治疗效果并减少不良副作用。
Although there are a large number of studies available for the evaluation of the therapeutic efficacy of targeted polymeric nanoparticles, little is known about the critical attributes that can further influence their uptake into target cells. In this study, varying cRGD ligand densities (0-100% surface functionalization) were combined with different poly(ethylene glycol) (PEG) spacer lengths (2/3.5/5 kDa), and the specific receptor binding of targeted core-shell structured poly(lactic-co-glycolic acid)/poly(lactic acid)-PEG nanoparticles was evaluated using alpha(v)beta(3) integrin-overexpressing U87MG glioblastoma cells. Nanoparticles with 100% surface functionalization and short PEG2k linkers displayed a high propensity to form colloidal clusters, allowing for the cooperative binding to integrin receptors on the cellular membrane. In contrast, the high flexibility of longer PEG chains enhanced the chance of ligand entanglement and shrouding, decreasing the number of ligand-receptor binding events. As a result, the combination of short PEG2k linkers and a high cRGD surface modification synergistically increased the uptake of nanoparticles into target cells. Even though to date, the nanoparticle size and its degree of functionalization are considered to be the major determinants for controlling the uptake efficiency of targeted colloids, these results strongly suggest that the role of the linker length should be carefully taken into consideration for the design of targeted drug delivery formulations to maximize the therapeutic efficacy and minimize adverse side effects.